Polatuzumab vedotin (DCDS4501A), a novel, targeted anti-cancer agent being developed by Genentech/Roche, is a first-in-class anti-CD79b antibody-drug conjugate or ADC currently being investigated for the treatment of several subtypes of non-Hodgkin lymphoma (NHL).

Results of a randomized phase II clinical trial, sponsored by Hoffman-LaRoche, shows that adding bendamustine and rituximab (MabThera®; Roche | Rituxan®; Genentech) to polatuzumab vedotin, significantly improved response and survival rates in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Early results led to a U.S. Food and Drug Administration (FDA) breakthrough therapy status and EMA PRIME designation.

Laurie Helen Sehn, MD, at the BC Cancer Agency in Vancouver, Canada, noted in a presentation earlier this month during annual meeting of the American Society of Clinical Oncology (ASCO), that the improvement in overall survival in patients with relapsed/refractory diffuse large B-cell lymphoma is clearly remarkable. [1]

“Based on these [..] results [of the trials], polatuzumab vedotin has received breakthrough therapy designation and priority medicines designations for [the treatment of patients with] relapsed or refractory DLBCL,” Sehn noted. However, in contrast, the study results demonstrated that, in short-term follow-up, there is no clinical improvements in a cohort of follicular lymphoma (FL) patients.

CD79b The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies.[2] Polatuzumab vedotin is thought to bind to CD79b, triggering internalization of the drug into the cells. This targets the cytotoxic, small-molecule chemotherapeutic payload, which is attached to the monoclonal antibody, to these B-cells. Based on an abundance caseload, this process is thought to maximize tumor cell death while, at the same time, potentially minimizing the effects on normal healthy cells.[3][4] Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics proprietary antibody-drug conjugate technology.

Trial design The multicenter, open-label study of polatuzumab vedotin administered by intravenous (IV) infusion in combination with standard doses of bendamustine and rituximab or obinutuzumab in participants with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma.[5]

The study comprises two stages. The first stage is a Phase Ib safety run-in stage. The second stage is a Phase II stage. The anticipated time on treatment was 18 weeks for participants with diffuse large B-cell lymphoma and 24 weeks for participants with relapsed or refractory follicular lymphoma.

Sehn and colleagues included a cohort of 80 patients with diffuse large B-cell lymphoma. These patients were randomized to receive bendamustine and rituximab or polatuzumab vedotin + bendamustine and rituximab for 6 planned 21-day cycles.

The researchers also randomized another cohort of 80 patients with relapsed or refractory follicular lymphoma to receive bendamustine and rituximab or polatuzumab vedotin + bendamustine and rituximab for 6 planned 28-day cycles.

The primary endpoint was complete response (CR) assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) at 6 to 8 weeks after the end of treatment.

Study results A total of 40% of patients with diffuse large B-cell lymphoma treated with polatuzumab vedotin + bendamustine and rituximab achieved complete response at the end of treatment, versus 15% of BR-treated patients (P=0.012).

According to Sehn, the improvement of complete response translated into a significantly higher progression-free survival (PFS) (6.7 months for polatuzumab vedotin + bendamustine and rituximab vs. 2.0 months for bendamustine and rituximab, P<0.0001) and overall survival (11.8 months versus 4.7 months, P=0.0008). Furthermore, regardless of the number of prior lines of treatment for diffuse large B-cell lymphoma, and regardless of relapsed versus refractory status, FDG-PET CR rates were higher in the polatuzumab vedotin + bendamustine and rituximab arm.

By contrast, in the relapsed or refractory follicular lymphoma cohort, the FDG-PET CR rate was high for both arms, at 69% for polatuzumab vedotin + bendamustine and rituximab and 63% for bendamustine and rituximab. Shen noted that there was no significant difference in progression-free survival (P=0.58) with relatively short-term follow-up.

Adverse events The most common grades 3 – 5 adverse events for both diffuse large B-cell lymphoma and patients diagnosed with follicular lymphoma were higher in the polatuzumab vedotin + bendamustine and rituximab arm than the bendamustine and rituximab arm and included cytopenias, febrile neutropenia, and infections.

Other observed serious adverse events were also higher in the polatuzumab vedotin + bendamustine and rituximab arm and included febrile neutropenia for both follicular lymphoma and diffuse large B-cell lymphoma patients and infection for patients with follicular lymphoma. Finally, a total of 5% of patients with follicular lymphoma and 18% of diffuse large B-cell lymphoma had a grade 5 event.

Conclusion Commenting on the study results, Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, NY noted that whether or not polatuzumab vedotin will change treatment paradigms for patients with diffuse large B-cell lymphoma may, potentially be answered by the ongoing, randomized phase III POLARIX study. This study compares polatuzumab plus R-CHP to R-CHOP in patients with previously untreated diffuse large B-cell lymphoma.[6][7]

Peter Hofland, Ph.D is the Executive Editor of ADC Review, Journal of Antibody-drug Conjugates, a comprehensive digital platform and peer reviewed publication focusing on news and information about innovative therapies such as Antibody-drug Conjugates (ADCs). Hofland contributes articles on the advances in ADCs - from initial discovery to approved drug. He is also a contributor to Onco'Zine and The Onco'Zine Brief. For more information about Hofland, check his ORCID profile here.

ADC Review, Journal of Antibody-drug Conjugates (ISSN 2327-0152) is an international peer-reviewed publication designed to serve the needs of a diverse community of individuals including academia, life sciences, pharma, research, clinicians and physicians. Along with regulatory affairs, we also cover government authorities and representatives from payers to policymakers.